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Twin Studies in Medical Genetics

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Twin Studies in Medical Genetics 7. TWIN STUDIES IN MEDICAL AND CLINICAL GENETICS TWIN STUDIES IN MEDICAL GENETICS P. PROPPING, F. VOGEL Institute of Anthropology and Human Genetics, University of Heidelberg, German Federal Republic It is the aim of twin studies to obtain results which are not only valid for twins, but apply to the whole population. Therefore the following questions have to be answered first: do twins differ from non- twins in the trait under study ? Do different nongenetic factors act upon MZ and DZ twins which alter the probability of manifestation of a trait, even before birth ? There are important differences in embryo- genesis and placental blood flow in mono- and dichorionic twins; this can influence the normal fetal development. Therefore the value of twin studies alone in analysing the genetic component in the etiology of congenital malformations is rather ambiguous. Twin studies beyond the newborn period can be classified into four approaches: (1) Case reports; (2) Accumulated case reports; (3) Limited representative sample; (4) Unlimited representative sample. The most frequent systematic method in medical genetics is the establishment of all twins in a defined population of probands {3). Another successful application in the last few years has been in pharmacogenetics. Although no simple mode of inheritance could be dis­ covered, it was possible to estimate the genetic component within the interindividual variability of the metabolism of certain drugs {nortriptyline, antipyrine, phenylbutazone, ethanol). Now, additional non- twin research is needed to work out single factors within the observed polygenic systems. We will limit our considerations on " Twins in Medical Genetics " to the following aspects: 1. Limitations of the twin method due to peculiarities in prenatal development; 2. Methodical possibilities of systematic twin research in traits which are alternatively distributed, e.g., diseases; 3. Examination of normal twins as a tool in pharmacogenetics. The aim of twin studies is to obtain results which do not only apply to twins but to the whole pop­ ulation. Therefore, the following question has to be answered first: Do twins differ from nontwins in the trait under study ? In spite of the peculiarities of the development of multiple zygotes during early embryogenesis, there is no doubt that, from the genetic point of view, twins are comparable to nontwins. Nevertheless, the comparison of a number of physiological parameters shows that there are differences between twins and nontwins: twins suffer from a higher frequency of abnormalities during pregnancy and at birth than single babies; they weigh less at birth, which can only partly be attributed to the shorter duration of gestation; the stillbirth rate and infant mortality in early life are considerably higher in multiple births than in single ones; in later years twins are more frequent among mentally defective patients than would be expected. The reasons for mental retardation may at least in part be traced back to the peculiarities during pregnancy and birth. If there are differences between twins and nontwins owing to various prenatal developments, the second question has to be: Do different nongenetic factors act upon MZ and DZ twins which alter the proba­ bility of manifestation of a certain trait, even before birth ? It is important to know this, because the twin method assumes that the two different types of twins are exposed to the same environmental factors. Again, weight at birth can serve as a simple analysable parameter. In a recent extensive survey, Corney et al. (1972) compared the average birth weights CODEN: AGMGAK 25 249 (1976) — ISSN: 0001-5660 DownloadedActa from Genet. https://www.cambridge.org/core Med. Gemellol. (Roma. IP )address: 25: 249-25 170.106.39.2198 , on 06 Oct 2021 at 17:44:05, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0001566000014215 250 P. PROPPING, F. VOGEL MALES FEMALES ( 304) ( 268) 2659 g 2547 g DICHORIONIC MONOCHORIONIC DICHORIONIC MONOCHORIONIC (196) (108) (162) (106) 2703 g 2579 g 2577g 2500 g DZ MZ MZ DZ MZ MZ 160) (36) (108) (1U) (18) (106) 2728 g 2595 g 2579 g 2601 g 2385g 2500 g Fig. 1. Mean birth weight of like-sexed twin subjects (survivors only), classified by sex, placentation, and zygosity. Numbers in parentheses. (From Corney et al. 1972). of 572 individuals from twin pairs of the same sex, classified by sex, placentation and zygosity. Fig. 1 not only shows that MZ twins of both sexes weigh less than DZ twins, but also that the type of the placenta has no effect on the mean birth weight of the surviving individuals. Therefore, it appears likely that zygosity, rather than placentation, is responsible for the differences in birth weight (Corney et al. 1972). But, when individuals within the (always MZ) monochorionic pairs are compared, greater differences come to light. In its extreme manifestation, these MZ twins differ in size by more than 1000 g (Benirschke and Kim 1973). Such differences may be the result of arteriovenous anasto­ moses which are assumed to be the basis of the chronic «transfusion syndrome ». These very common anastomoses can lead to chronic malnutrition with a reduction of cytoplasmic mass of parenchymal organs, as well as markedly reduced hemoglobin and serum protein values in the donor twin (Benir­ schke and Kim 1973). Since more than 20% of the MZ twins have only one chorion (Potter 1963), the transfusion syndrome can account for the greater intrapair differences at birth which do not arise in DZ twins. Therefore, the twin method cannot be applied to those traits in which the two types of twins are influenced in different ways by the intrauterine environment. In medical genetics, the twin method is preferentially used in cases where a multifactorial system of inheritance is supposed to exist. Are there congenital diseases to which the peculiarities of the twin pregnancy contribute? The following data show that this has to be assumed, at least for some types of congenital malformation. Table 1 shows congenital malformation frequencies in twins and in single births compiled from dif­ ferent series. Although frequencies of congenital malformations vary greatly in the five series, presum­ ably due to different definitions, on the whole these anomalies appear to be more frequent in twins than in singletons in every analysis published. This is already a sign of differences present during the gestation period. This tendency is more obvious when particular types of malformation are taken into consideration. At least, as far as the diseases are concerned such as congenital heart disease, anencephalus, hydrocephalus, cleft lip or palate, the risk in twins is higher than in single births. Table 2 shows frequencies of malformation in singletons compared with like-sexed and unlike-sexed twins. In all four cases, the individual risk is higher in same-sexed than in opposite-sexed twins. Downloaded from https://www.cambridge.org/core. IP address: 170.106.39.219, on 06 Oct 2021 at 17:44:05, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0001566000014215 TWIN STUDIES IN MEDICAL GENETICS 251 Table 1. Incidence of congenital malformations in twins and singletons per 1000 births Source Approximate sample size Incidence in singletons Incidence in twins Hendricks 1966 ~ 35,000 33 106 Stevenson et al. 1966 421,000 12.7 14.4 Hay and Wehrung 1970 10,200,000 5.8 6.2 Onyskowova et al. 1971 240,000 13.2 26.4 Emanuel et al. 1972 25,000 13.2 23.2 Table 2. Incidence of selected congenital malformations in twins and singletons per 1000 births Type of mal­ Incidence in Incidence in twins formation Source* singletons Total Like sexed Unlike sexed Congenital heart a 0.74 1.65 1.82 1.27 disease b 2.8 6.3 c 0.59 0.71 0.81 0.49 Anencephalus a 0.92 1.24 1.52 0.64 b 1.3 1.2 c 0.23 0.37 0.45 0.22 Hydrocephalus a 0.61 0.72 0.91 0.32 b 1.0 3.1 c 0.30 0.40 0.45 0.31 Cleft lip and/or a 1.21 0.34 1.68 0.64 cleft palate b 0.8 0.4 c 1.11 1.07 1.10 1.01 * a = Stevenson et al. 1966; b = Edwards 1968; c = Hay and Wehrung 1970. This points to the fact that MZ twins are more frequently encountered than DZ ones. The actual figure concerning risk, however, must be higher, because only about 50% of the like-sexed twins are MZ. The reason for the greater portion of MZ among malformed twin individuals could be the consequence of the " transfusion syndrome ". This conclusion is supported by the fact that, in the majority of cases, malformation arises in only one of the twins. Unfortunately, there are no series on congenital malformation in twins available in which the type of placentation is taken into account. Twin studies on congenital malformation using unselected cases show relatively low concordance rates in MZ twins. Table 3 summarizes the available twin data on congenital cleft lip and/or cleft palate (Jorgensen and Gabka 1971). Table 4 shows the concordance rates of 5 twin studies on congen­ ital cardiac malformation. The higher concordance rates in MZ twins in both examples indicate a genetic component. It has to be supposed, however, that the concordance rate in the monochorionic twins within the MZ group is lowered due to differential developmental conditions of the twin indi­ viduals. A thorough analysis of discordant MZ twins, which can be so valuable in other diseases, is not possible in cases of congenital malformation unless we know the placental type.
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